Non-coding RNAs (ncRNAs) have emerged as key players in genetic regulatory systems. Sm-class RNAs constitute a group of ncRNAs with essential roles in important metabolic processes such as pre-mRNA splicing and 3??-end processing. However, additional Sm-class RNAs have been identified, and we have obtained evidence that they function in gene regulation. We now propose to characterize the targets and mechanisms of action of this distinct new functional subset of Sm-class RNAs. This proposal focuses on determining the functions of novel Sm-class RNAs of both viral and cellular origin. Herpesvirus saimiri (HVS) is an oncogenic ?-herpesvirus that infects T cells and causes aggressive lymphomas and leukemias in New World primates. HVS expresses seven Sm-class RNAs called HSURs (Herpesvirus saimiri U-rich RNAs), of unknown function. Preliminary studies show that HSURs 1 and 2: i) promote the survival of HVS-transformed T cells, ii) associate with actively translated host mRNAs, iii) also associate with host miRNAs (miR-27, miR-16, and miR-142-3p) and AU-rich element (ARE)-binding proteins, and iv) downregulate the target mRNAs. We therefore hypothesize that HSURs 1 and 2 repress target mRNAs by recruiting inhibitory miRNA and ARE-binding protein complexes. We further hypothesize that these activities rewire key host pathways to inhibit apoptosis of latently infected cells. Our preliminary data also identify several new Sm-class RNAs that appear to be expressed in human cell lines. We now propose to test how viral Sm- class RNAs contribute to HVS-mediated T cell transformation, and to characterize the functions of novel human Sm-class RNAs. This proposal combines biochemistry, genetics, and high-throughput sequencing with the aim of defining which cellular pathways are likely regulated by HVS through HSURs 1 and 2 in latently infected cells (Aim 1), determining how HSURs select and repress their target mRNAs (Aim 2), and characterizing the functions of newly identified human Sm-class RNAs (Aim 3). Completion of these aims will deepen our understanding of host-virus interactions, potentially leading to better therapies to combat these infections. More importantly, it will also expand our understanding of an understudied class of ncRNAs and illuminate a novel mechanism of regulation likely used in the broad range of eukaryotes that express Sm-class ncRNAs.